ABSTRACT Accumulating evidence shows inflammation strongly influences the development and treatment of depression, a debilitating disease with a lifetime incidence of ~20%. Markers of Inflammation often are increased in the serum of depressed patients, interferon administration can induce depression, psychological stresses that can induce depression increase inflammatory cytokines in humans and rodents, administration of inflammatory cytokines induces depression-like behaviors in rodents, in humans increased cytokines associated with a mild stimulation of the primary host defense system has negative effects on emotions, antidepressants have anti-inflammatory effects, and immune activation in patients with major depression is associated with resistance to antidepressant treatment. Therefore, in order to understand and design improved therapeutics for depression, it is important to identify mechanisms regulating neuroinflammation, inflammatory molecule accumulation in the CNS. Glycogen synthase kinase-3 (GSK3) recently was found to be a powerful regulator of cytokine production in the periphery. We extended this to the CNS, e.g., showing that GSK3 inhibitors reduce by >90% the production of the proinflammatory cytokine interleukin-6 in astrocytes and microglia. We also found that GSK3 inhibitors promote tolerance to inflammation, down-regulating inflammatory responses to repeated inflammatory stimuli, which may be particularly important in controlling chronic inflammation that is likely associated with mood disorders. GSK3 also has profound influences in mood disorders, it is inhibited by mood stabilizers and antidepressants, pharmacological or genetic reduction of GSK3 activity reduces depression-like behaviors in rodents, and evidence in postmortem brain samples and serum from humans indicate GSK3 is abnormally active in mood disorders. We recently found GSK3 is activated in mouse brain by the learned helplessness model of depression. Taken together, these findings suggest that the pro-inflammatory action of GSK3 may contribute to its promotion of mood disorders, and that the therapeutic actions of mood stabilizers and antidepressants that inhibit GSK3 may involve anti-inflammatory effects. Thus, studies of the inflammation system provide a model system to study how GSK3 regulates key processes that are likely involved in mood disorders: epigenetics, tolerance, and behavior. These aims provide independent but associated goals that will identify new mechanisms by which dysregulated GSK3 can contribute to mood disorders and identify how therapeutic interventions ameliorate these outcomes. Specific Aim 1 will test the hypothesis that GSK3 regulates innate and adaptive immune system in the brain during depressive-like behavior. Specific Aim 2 will test the hypothesis that GSK3 regulates epigenetics, using changes induced by inflammatory stimuli as a model. Specific Aim 3 will test the hypothesis that GSK3 promotes depression-like behavioral responses to inflammatory and environmental stress.